Modification of proteins with polyethylene glycol (“PEGylation”) has the potential to increase residence time and reduce immunogenicity in vivo. For example, Knauf et al., J. Biol. Chem., 263: 15064-15070 (1988) reported a study of the pharmacodynamic behavior in rats of various polyoxylated glycerol and polyethylene glycol modified species of interleukin-2. Despite the known advantage of PEGylation, PEGylated proteins have not been widely exploited for clinical applications. In the case of antibody fragments, PEGylation has not been shown to extend serum half-life to useful levels. Delgado et al., Br. J. Cancer, 73: 175-182 (1996), Kitamura et al., Cancer Res., 51: 4310-4315 (1991), Kitamura et al., Biochem. Biophys. Res. Comm., 171: 1387-1394 (1990), and Pedley et al., Br. J. Cancer, 70: 1126-1130 (1994) reported studies characterizing blood clearance and tissue uptake of certain anti-tumor antigen antibodies or antibody fragments derivatized with low molecular weight (5 kD) PEG. Zapata et al., FASEB J., 9: A1479 (1995) reported that low molecular weight (5 or 10 kD) PEG attached to a sulfhydryl group in the hinge region of a Fab′ fragment reduced clearance compared to the parental Fab′ molecule.
Interleukin-8 (IL-8) is neutrophil chemotactic peptide secreted by a variety of cells in response to inflammatory mediators (for a review see Hebert et al. Cancer Investigation 11(6):743 (1993)). IL-8 can play an important role in the pathogenesis of inflammatory disorders, such as adult respiratory distress syndrome (ARDS), septic shock, and multiple organ failure. Immune therapy for such inflammatory disorders can include treatment of an affected patient with anti-IL-8 antibodies.
Sticherling et al. (J. Immunol. 143:1628 (1989)) disclose the production and characterization of four monoclonal antibodies against IL-8. WO 92/04372, published Mar. 19, 1992, discloses polyclonal antibodies which react with the receptor-interacting site of IL-8 and peptide analogs of IL-8, along with the use of such antibodies to prevent an inflammatory response in patients. St. John et al. (Chest 103:932 (1993)) review immune therapy for ARDS. septic shock, and multiple organ failure, including the potential therapeutic use of anti-IL-8 antibodies. Sekido et al. (Nature 365:654 (1993)) disclose the prevention of lung reperfusion injury in rabbits; by a monoclonal antibody against IL-8. Mulligan et al. (J. Immunol. 150:5585 (1993)), disclose protective effects of a murine monoclonal antibody to human IL-8 in inflammatory lung injury in rats.
WO 95/23865 (International Application No. PCT/US95/02589 published Sep. 8, 1995) demonstrates that anti-IL-8 monoclonal antibodies can be used therapeutically in the treatment of other inflammatory disorders, such as bacterial pneumonias and inflammatory bowel disease.
anti-IL-8 antibodies are additionally useful as reagents for assaying L-8. For example, Sticherling et al. (Arch. Dermatol. Res. 284:82 (1992)), disclose the use of anti-IL-8 monoclonal antibodies as reagents in immunohistochemical studies. Ko et al. (J. Immunol. Methods 149:227 (1992)) disclose the use of anti-IL-8 monoclonal antibodies as reagents in an enzyme-linked immunoabsorbent assay (ELISA) for IL-8.